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The Rise of Stem Cell Toxicology
Francesco Faiola,* Nuoya Yin, Xinglei Yao, and Guibin Jiang
State Key Laboratory of Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing 100085, China
these issues can greatly affect the generation and interpretation
of toxicity data. However, as described below, new stem cell
technologies for the in vitro analyses of pollutants’ potential
hazardousness, allow scientists to move past these problems.
The first successful derivation of human embryonic stem
cells (hESCs),3 and the discovery of human induced
pluripotent stem cells (iPSCs),4 have intrigued the scientific
community because of their potential to immensely advance
many research fields. In particular, these breakthroughs are
revolutionizing the field of toxicology in such a way that we
need to create a new branch defined as “stem cell toxicology”
that encompasses the thorough investigation of the adverse
effects of substances on living organisms exclusively using stem
cells. Though this approach may seem limited, it is important to
remember that pluripotent stem cells have the capacity to
proliferate indefinitely in culture, and the ability to differentiate
into all cell types of an adult organism. These properties
therefore make them ideal for human toxicological studies on
various cell or tissue types. For instance, ESCs and iPSCs can
be used to evaluate acute toxicity, and although other cultured
cells types may be suitable for this type of assay, pluripotent
stem cells have often been demonstrated to be more sensitive
he field of environmental toxicology has been challenged
than somatic cells. The effects of a test material on fetal
in the last few decades by the exponential discovery of
development can also be assessed with stem cells by looking at
novel persistent pollutants and the relative lack of knowledge of
any abnormal differentiation phenotype. For example, ESCs can
their hazardousness to human health. At the same time, there
differentiate in vitro as three-dimensional aggregates called
has been increasing awareness of the urgency and necessity of
embryoid bodies (EBs), which mimic early embryonic
innovative, validated, and comprehensive assays to collect
developmental stages in vivo. This is the so-called embryonic/developmental toxicity assay. A third type of toxicity assay
toxicity data more relevant to humans. Since the onset of
where stem cells are very useful is the cell function assay.
toxicology science, we have heavily relied on animal tests.
Pluripotent stem cells are first differentiated into adult stem
Although these in vivo experiments have been refined in recent
cells or progenitor cells, and then into particular types of
years, they are still expensive, labor intensive, time-consuming,
terminally differentiated somatic cells. Subsequently, their
and accompanied by ethical issues. More importantly, Russell
cellular functions are assessed upon treatment with a chemical.
and Burch’s “high fidelity fallacy” theory postulates that toxicity
This is particularly important when the primary cells are very
assays with animals are not always applicable to human health
difficult to derive directly from animals or humans. All of these
due to interspecies variations, even when primates are used. A
assays are reviewed in.5 A growing concern about pollution is
prototypical example is the case of the drug thalidomide,
its relationship to human reproduction. With pluripotent stem
proven to be highly teratogenic in humans even though it had
1
cells, we are able to investigate in vitro the potential effects of
passed all animal tests. This led to the introduction of in vitro
pollutants on our ability to reproduce. In fact, murine ESCs can
tests as alternatives to in vivo animal experiments (reviewed in
first be differentiated toward epiblast stem cells (EpiSCs), and
ref 2). In particular, the culture of human cells for toxicity tests,
then to germ cells. Similarly, hESCs can be differentiated
more directly relevant to human health, has been the primary
toward primordial germ cell-like cells. We can then test whether
solution to the obvious fact that humans cannot be used for in
these germ cells function correctly under various conditions.
vivo studies. However, the direct derivation of some types of
In conclusion, stem cell toxicology allows for the concurrent
primary human cells, can be extremely invasive or simply
assessment of many forms of toxicity including acute,
impossible, and even if successful, the ability of primary cells to
embryonic, developmental, organ, reproductive, and functional.
be cultured and expanded in vitro is limited. Conversely,
It also provides a unique and widely applicable system for
immortalized or cancer cell lines can be readily grown and
amplified in dishes; nevertheless, they may no longer be
representative of the cells of origin because of accumulating
Received: March 27, 2015
mutations or altered cell functions, for example. Collectively,
Published: May 5, 2015
T
© 2015 American Chemical Society
5847
DOI: 10.1021/acs.est.5b01549
Environ. Sci. Technol. 2015, 49, 5847−5848
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Environmental Science & Technology
Figure 1. Stem cell-based toxicity assays. ESCs: Embryonic stem cells. iPSCs: Induced pluripotent stem cells. EBs: Embryoid bodies. PGCs:
Primordial germ cells.
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studies that are directly relevant to human health without the
use of animal models (Figure 1). Although we have been
stressing the importance of using human pluripotent stem cells
in toxicology, we should also rely on murine ESCs and iPSCs,
as well as human and mouse adult stem cells, to take advantage
of all the scientific and technical advancements already achieved
with them that we have not yet accomplished with the human
and pluripotent counterparts. Indeed, the very first validated
stem cell toxicity assay, the embryonic stem cell test (EST), was
designed with murine cells by the European Center for the
Validation of Alternative Methods (ECVAM) in 2002
(reviewed in ref 5). This simple test measured cell viability
and the propensity to differentiate into clusters of beating
cardiomyocytes; however, it was based exclusively on mouse
ESCs using a single differentiation procedure, and without
molecular end points to interpret toxicity. Thus, to
appropriately define stem cell toxicology, we must include
human stem cells to broaden the evaluation of toxicity.
Nevertheless, before stem cell toxicology allows us to reach
the goal of animal test-free toxicology, we need to not only
perfect the myriad of traditional and novel stem cell
differentiation procedures, but also to establish guidelines for
stem cell-based toxicity assays. These should include universal
procedures with validated molecular end points, which will
greatly enhance the interpretation of toxicity data. Importantly,
iPSC technology will enable us to assess toxicity without the
ethical issues associated with the derivation and use of hESCs,
but with the added benefit of the potential for personalized
toxicology.
■
REFERENCES
(1) Mellin, G. W.; Katzenstein, M. The saga of thalidomide.
Neuropathy to embryopathy, with case reports of congenital
anomalies. N. Engl. J. Med. 1962, 267, 1184−92.
(2) Jennings, P. The future of in vitro toxicology. Toxicol. In Vitro
2014, DOI: 10.1016/j.tiv.2014.08.011.
(3) Thomson, J. A.; Itskovitz-Eldor, J.; Shapiro, S. S.; Waknitz, M. A.;
Swiergiel, J. J.; Marshall, V. S.; Jones, J. M. Embryonic stem cell lines
derived from human blastocysts. Science 1998, 282 (5391), 1145−7.
(4) Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.;
Tomoda, K.; Yamanaka, S. Induction of pluripotent stem cells from
adult human fibroblasts by defined factors. Cell 2007, 131 (5), 861−
72.
(5) Mori, H.; Hara, M. Cultured stem cells as tools for toxicological
assays. J. Biosci. Bioeng. 2013, 116 (6), 647−52.
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected].
Notes
The authors declare no competing financial interest.
5848
DOI: 10.1021/acs.est.5b01549
Environ. Sci. Technol. 2015, 49, 5847−5848